This Funding Opportunity Announcement (FOA) issued by the
National Institute of General Medical Sciences (NIGMS), National Institutes
of Health (NIH), solicits applications that propose genetic, physiological,
and ecological studies designed to reveal the basic principles and mechanisms
that govern the symbiotic systems dynamics of host-associated microbial
communities.

Key Dates

Posted Date

October 17, 2012

Open Date (Earliest Submission Date)

December 14, 2012

Letter of Intent Due Date(s)

December 14, 2012

Application Due Date(s)

January 15, 2013, by 5:00 PM local time of applicant
organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

June-July, 2013

Advisory Council Review

October, 2013

Earliest Start Date

December 1, 2013

Expiration Date

January 16, 2013

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed to do otherwise (in
this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any
program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the
Application Guide, follow the program-specific instructions. Applications that
do not comply with these instructions may be delayed or not accepted for review.

This Funding Opportunity Announcement (FOA) issued by the
National Institute of General Medical Sciences (NIGMS), National Institutes of
Health (NIH), solicits applications that propose genetic, physiological, and
ecological studies designed to reveal the basic principles and mechanisms that
govern the symbiotic systems dynamics of host-associated microbial communities.

Background

Microbes comprise over 90% of the cells of the human body,
forming distinctive communities in different parts of the body. These complex
and dynamic communities of microbes (the human microbiota) have a major impact
on human health – by promoting proper development of host organs, stimulating
development of the immune system, providing nutrients to the human host, and
excluding potential pathogens. Alteration of indigenous microbial communities
can cause pathological conditions, including periodontal disease, ulcers, and
secondary pneumonia. Recent studies indicate that microbial communities may
influence many other aspects of human health, from obesity to chronic diseases
like atherosclerosis. Rather than the traditional concept of “one microbe, one
disease,” it has become clear that some diseases are polymicrobial – caused by
altered communities of microbes. The microbial communities of the gut, in
particular, have important implications for health by affecting metabolism of
food and drugs. The gut inhabitants transform chemicals we consume into
beneficial, harmless, and harmful compounds, thereby influencing the level of
human exposure to pharmaceutically active compounds.

Given the key role of indigenous microbial communities in
influencing human health and disease, personalized medicine will likely require
an understanding of the microbial communities associated with the individual,
in addition to an individual’s genome sequence. However, such approaches to
personalized medicine are currently beyond our capacity, primarily because the
interactions and processes within the communities, and between communities and
the host, are complex and poorly understood. It is often possible to identify
the representative microbes in a particular environment, and significant
progress has been made, due in large part to the NIH Roadmap Human Microbiome
Project (HMP) (http://nihroadmap.nih.gov/hmp/), in
identifying the microbial community composition from a number of human niches
and reflecting a handful of normal and disease states. However, there is still
a need to provide insight into the basic physiological and ecological
principles that govern the formation and persistence of host-associated
microbial communities. These principles most likely will be elucidated by
hypothesis-based research, using systems and methods that are optimal for the
task. It is the responsibility of applicants to identify such systems and
methods, and articulate the questions that are most amenable to analysis.

Applicants may propose the use of human or simple-to-complex
animal models or synthetic systems with a direct link to the host, but must
describe how the model system proposed allows one to ask a basic biological
question that is relevant to this FOA. One might reasonably expect that these
studies will reveal evolutionary conserved principles that address questions
such as: what factors distinguish microbes that comprise the core of the
community from those that are transient; what are the key characteristics of
niche environments that favor particular assemblages of microbes; by what means
do the microbes in the community interact with each other and with the host,
and how do the communities evolve – i.e., what is their natural history?

Research
Objectives

To advance the nascent science of host-associated microbial
community ecology, this FOA solicits research grant applications for innovative
genetic, physiological, and ecological studies that are designed to reveal the
basic principles and mechanisms that govern host-associated microbial community
structure and function. Applications are solicited in the following areas, but
are not limited to:

Community
dynamics

The principles that explain how communities develop
population structures that both resist and recover from perturbation
(robustness) are not well understood. Among the possible approaches to
analyzing these properties could be innovative genetic techniques, including
metagenomics and directed mutations, in conjunction with computational
modeling. Direct experimental tests of predictions about how the flow of
metabolites, signaling molecules, or genetic information between host and
members of the microbial community contribute to community stability are
encouraged. Perturbations of community structure could also provide key
evidence for the existence of stabilizing networks that account for robustness
to change. New approaches to adapt mutational approaches to poorly
characterized microbial communities are also encouraged.

Community
physiology

Nutrient flow in microbial communities is complex,
and it will be essential to develop ways to measure it in order to understand
community dynamics. It is likely that the overall physiology of the
host-microbe community system cannot be understood by focusing solely on the
individual members of the system. The exchange of metabolites, signaling
molecules, and energy sources between microbes and the host comprises a complex
network. Understanding how microorganisms contribute to or draw from the
available nutrient pool, the dependence of this pool on changing
microenvironments and the influence of spatial gradients, how microorganisms
cooperate to synthesize metabolites, and how community members compete for
nutrients is of critical importance within the scope of this announcement.
Equally important is understanding how the host’s physiology responds to, and
in turn influences, the microbial component. Studies that examine both host and
microbial symbionts provide powerful insight into the complex reciprocity of
the “holobiont” and require innovative approaches, which may include new
analytical techniques, genetic methods, and/or use of network analysis and
mathematical modeling/simulation.

Community
genetic interactions

In addition to the ability of microbes to exchange
signals that affect gene expression, share metabolites, and create nutrient and
other chemical gradients, microbes also exchange genetic material. Recent
metagenomic studies on bacterial viruses indicate that there is a surprising
amount of exchange of genetic information between microbes in natural
environments. Innovative methods to study the dynamics and consequences of this
gene flow in host-microbe communities are encouraged.

Model
systems

Model systems could have significant advantages for
the discovery of common principles of host-associated microbial community
structure and function, in as much as both host and microbes can be subject to
high resolution morphological, genetic, physiological, and biophysical analysis.
Model systems also can be platforms for developing novel, effective tools for
these studies. The further development of existing model systems and the
development of new systems that are particularly well suited to address
fundamental questions of host-community structure and function are encouraged.

Development
of new technologies

Many of the questions regarding the physical and
functional architecture of microbial communities may not be addressable with
existing methods, demanding new technological advances. For example, single
cell tracking and functional analysis in complex assemblages such as biofilms
may require advances in microscopy and gene tagging. Improvements also are
likely to be required in the use of isotopically labeled substrates to map
metabolite flows in complex mixtures of organisms, and their hosts. The
architecture of microbial communities in unique micro-niches within the host
may have to be explored at fine resolution to provide the basis for elucidating
the rules of community assembly and evolution. Overall, the technology
development proposed must be transformative, and it must be in direct support
of hypothesis testing.

In summary, this FOA will support research on fundamental
principles and mechanisms that govern the symbiotic systems dynamics of
host-associated microbial communities (where community is defined as two or
more phenotypically distinct populations of microbe). NIGMS recognizes that
most of these questions are complex in nature, and applicants are encouraged to
utilize interdisciplinary approaches, including
bioinformatic/computational/modeling, and/or experimental manipulations to the
study of host-associated microbial community ecology. This FOA will not
support: a) narrowly focused mechanistic studies; b) descriptive studies that
are designed solely to carry out metagenomic sequencing or surveys of microbial
diversity; c) studies that have a major focus on a specific disease or
host-pathogen dynamics (as opposed to basic principles of the symbiotic systems
dynamics of host-microbe community); and d) studies that are likely to yield
only incremental information.

Section II. Award Information

Funding Instrument

Grant: A support mechanism
providing money, property, or both to an eligible entity to carry out an approved
project or activity.

Applicant organizations must complete the following registrations
as described in the SF424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.

System for Award Management (SAM) – must maintain an active entity registration (formerly CCR
registration), to be renewed at least annually. Use the SAM.gov “Manage Entity”
function to manage your entity registrations. See the Grants Registration User
Guide at SAM.gov for additional information.

All Program Directors/Principal Investigators (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the
same as one already reviewed within the past thirty-seven months (as described
in the NIH
Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

Resubmission applications (from RFA-GM-13-001 ONLY) may be submitted, according to the NIH Policy on Resubmission
Applications from the SF 424 (R&R) Application Guide.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide, with the following modification:

GWAS
Sharing Plan is not applicable for this FOA.

Appendix

Do not use the Appendix to
circumvent page limits. Follow all instructions for the Appendix as described
in the SF424 (R&R) Application Guide.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies
described in the NIH Grants
Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications
before the deadline to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application before the deadline in the eRA
Commons to ensure accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the
SF424(R&R) Application Package. Failure to register in the Commons
and to include a valid PD/PI Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application
Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations,
NIH. Applications that are incomplete and/or nonresponsive will not be
reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD(s)/PI(s), do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the
application as now presented, taking into consideration the responses to
comments from the previous scientific review group and changes made to the
project.

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following
Resource Sharing Plans, or the rationale for not sharing the following types of
resources, are reasonable: 1) Data
Sharing Plan; and 2) Sharing
Model Organisms.

Budget and Period of Support

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by NIGMS, in
accordance with NIH peer
review policy and procedures, using the stated review
criteria. Assignment to a Scientific Review Group will be shown in the eRA
Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact
score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in
response to this FOA.

Applications will be assigned to the appropriate NIH
Institute or Center. Applications will compete for available funds with all
other recommended applications submitted in response to this FOA. Following
initial peer review, recommended applications will receive a second level of
review by the National General Medical Sciences Advisory Council. The following
will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

When multiple years are involved, awardees will be required
to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR)
and financial statements as required in the NIH Grants
Policy Statement.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and
405 of the Public Health Service Act as amended (42 USC 241 and 284) and under
Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.